Alzheimer's Disease (AD) is a progressive neurodegenerative disease highlighted by two pathological hallmarks: extracellular senile plaques containing amyloid [unreadable] aggregates and intracellular neurofilbrillar tangles consisting of hyperphosphorylated microtubule-associated tau proteins. Aggregated A[unreadable] fibrils constitute the core of neuritic plaques and are believed to be a major culprit for neurodegeneration and subsequent cognitive abnormalities of AD brains. Recent studies, however, indicate that A[unreadable] molecules exert adverse effects on neuronal functions independent of cell death. Specifically, soluble A[unreadable] oligomers were found to exhibit severe inhibition of synaptic functions and plasticity, indicating that these intermediate A[unreadable] aggregates, not the fibrils, may be responsible for synaptic deficits in AD brains. At this moment, how A[unreadable] molecules impair synaptic functions remain unknown. It is also not clear whether A[unreadable] molecules exert any adverse effects on other cellular functions independent of cell death. We find that soluble A[unreadable] molecules acutely impair fast transport of mitochondria through a specific signaling pathway involving GSK3[unreadable]. Our findings are distinct from the long-term toxic effects of A[unreadable] on neurons and do not involve cell death. Given that mitochondrial trafficking and localization are essential for many cellular functions including synaptic activities, their inhibition by A[unreadable] could play an important role in AD-related dysfunctions of neuronal connectivity. This R21 application is based on these exciting findings and aims to further investigate acute effects of A[unreadable] on neuronal trafficking of mitochondria and other cellular organelles. The central hypothesis is that A[unreadable] molecules exhibit acute inhibition on neuronal trafficking, which may constitute one of the early A[unreadable] adverse effects leading to the disruption of normal neuronal functions and development of AD-related neuronal dysfunctions. The proposed study will specifically take advantage of our high-resolution imaging expertise, the manipulability of cultured hippocampal neurons, and our experience in neuronal signal transduction to investigate the following two aims: (1) To characterize and investigate the acute inhibitory effects of A[unreadable] molecules on trafficking of mitochondria and other organelles; (2) To study the cellular mechanisms underlying A[unreadable] acute impairment of mitochondrial transport involving the GSK3[unreadable] signaling pathway. The goal of this study is to identify the significant adverse effects of A[unreadable] molecules on important neuronal functions that may contribute to AD pathological conditions. Results from this study will not only advance our understanding of AD cellular mechanisms but also provide the signaling mechanisms that can be targeted for drug development for AD prevention and treatment. [unreadable] [unreadable]